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3323 Relapse Prophylaxis Post-Haploidentical Bone Marrow Transplantation and Cyclophosphamide (Haplo/Cy) By Infusion of Donor-Derived Expanded/Activated Gd T Cells: A Phase I Trial

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Acute Myeloid Malignancies, AML, Biological therapies, APL, Clinical Research, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, Myeloid Malignancies, Transplantation
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Joseph P. McGuirk, DO1, Sunil H Abhyankar, MD1,2, Trishna Goswami, MD3*, Rupal Soder, PhD4*, Mariska ter Haak3*, Tyce Bruns5*, Samantha Langford Youngblood, BS6* and Lawrence S. Lamb Jr., PhD3

1Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
2University of Kansas Cancer Center, Westwood, KS
3In8bio, Inc., New York, NY
4Midwest Stem Cell Therapy Center, Kansas City, KS
5Clinical Trial Office, University of Kansas Medical Center, Fairway, KS
61500 First Avenue North, Suite 103, In8bio, Birmingham, AL

Background: Effector γδ T cells immediately recognize and kill malignant cells in a broad-based non-MHC restricted manner. Increases in circulating donor-derived γδ T cells during post-bone marrow transplant (BMT) recovery have been significantly associated with improved disease-free survival (DFS). Relapse post Haplo/Cy BMT occurs in approximately 45% of patients. We sought to mitigate relapse in this context by expanding, activating, and infusing donor-derived haploidentical γδ T cells. We now report preliminary clinical and biologic correlative findings from the first cohort of patients who have been treated with ex vivo expanded and activated donor γδ T cells (EAGD). This single-center Phase I clinical trial represents the first systemic infusion of allogeneic EAGD cells in the post-BMT setting

Methods: Standard of care reduced-intensity flu/cy/TBI conditioning was followed by an unmanipulated bone marrow graft and 50mg/m2 Cy on days +3 and +4 post-transplant. EAGD were manufactured using the Miltenyi Prodigy bioreactor and cryopreserved. The product was infused intravenously within 5 days of neutrophil engraftment (ANC >500/µL X 3d). Peripheral blood was collected at EAGD infusion and monthly thereafter through day +90, with additional collections every 6 months through 1 year. Biologic parameters included multiparameter flow cytometric immunophenotyping and single cell cytokine analysis of the EAGD graft. Peripheral blood analysis includes leukocyte count and differential, immunophenotyping, and serum Th1/Th2/Th17 cytokine analysis. Primary endpoints include dose-limiting toxicities (DLT) and grade 3-4 adverse events while secondary endpoints include incidence of acute and chronic GvHD, relapse, and overall survival.

Results: Three patients have received the first dose level of 1 x 106 EAGD/kg. All three patients remain in morphologic complete remission at 26.5, 24.2, and 12.5 months post-BMT. One patient is receiving ongoing hypomethylating therapy for the occurrence of recipient chimerism. Grade 1-2 toxicities include constipation, CMV reactivation, emesis, fatigue, and hypomagnesaemia. Steroid-responsive cutaneous acute Grade I-II GVHD has been observed in all patients with one patient experiencing Grade II intestinal GvHD. No chronic GVHD, DLTs, treatment-related ≥ grade 3 adverse events, or cytokine release syndrome has occurred. EAGD grafts contained 88.7% - 99.2% Vγ9Vδ2+ γδ T cells with small populations of NK cells and <1.0 x 10 αβ T cells/kg. EAGD principally expressed Granzyme B, MIP1α, MIP1β, and IL-2.

Significant peripheral lymphodepletion persisted through the first 100 days post-BMT followed by slow recovery of CD4+, CD8+, γδ T and B cells. NK cells remained within the low normal range throughout. T cells transitioned from a CD45+CD27- effector phenotype to CD45RA CD27 central to effector memory phenotype as recovery progressed. CD3 CD4 CD25 FoxP3 Treg cells remained <3% of circulating T cells. Preliminary serum cytokine and chemokine analysis revealed predominant expression of IFNγ, IL-12p70, IP-10, RANTES and TNFα.

Conclusions: Early indications suggest that EAGD transfusion with the initial dose level of 1 x 106 EAGD/kg has manageable toxicity and an appropriate immune recovery profile with 3 of 3 patients alive and progression-free.

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03533816

Disclosures: McGuirk: Sana: Honoraria; CRISPR Therapeutics: Consultancy; In8bio, Inc.: Other: IIT Clinical Trial; Novartis: Consultancy, Honoraria; Orca Bio: Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Nextar: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding. Abhyankar: Talaris: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Research Funding, Speakers Bureau; Therakos: Consultancy, Research Funding, Speakers Bureau. Goswami: IN8Bio, Inc.: Current Employment. ter Haak: IN8Bio, Inc.: Current Employment. Youngblood: IN8Bio, Inc.: Current Employment. Lamb: IN8Bio, Inc.: Current Employment.

*signifies non-member of ASH